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Inflammatory Bowel Disease: Treatment

Jorge Amil Dias

Porto - PORTUGAL

jamildias@zonmail.pt

Objectives of treatment in IBD Differences UC CD

Disease activity Acute flares Persistent inflammation activity

Treatment goals Prevention of relapse and CRC

Prevention of strictures and penetrating complications

Immunomodulators and Biologics

Only when inadequate response to steroids

Early introduction?

Surgical outcomes “Curation” of disease

Immediate clinical benefit

Symptoms

New diagnosis

Remission Incomplete response

Loss of response / Recurring symptoms

Probability of IBD Crohn’s vs UC

Prognosis

Therapeutic adjustment

Prognosis

IBD or another cause for the

symptoms

Paediatric vs adult-onset CD

Pigneur B et al. Inflamm Bowel Dis, 2010

% of pts with active disease % of pts with immunosuppressants

Risk of surgery in CD

Childhood-onset CD Adult-onset CD

Pigneur B et al. Inflamm Bowel Dis, 2010

Frequent myths in Paediatric Ulcerative Colitis

• “U.C. is not a severe disease (≠ Crohn’s)”

• “Distal disease is usually mild”

• “U.C. is curable”

• “Mucosal healing is not important”

Extension of Ulcerative Colitis

16.4% 1.4%

Paediatric

Pancolitis E3

Left colitis E2

Proctitis E1

Adults

van Limbergen et al Gastroenterology 2008

Patients <16 yrs with UC ≤ 5 yrs of Dg > 5 yrs of Dg

Initial activity of Ulcerative Colitis

17% Mild

Moderate

Severe

Pediatric Adult

North American Pediatric IBD Collaborative Research Group

Evolution of Ulcerative Colitis

% without colectomy

Time to colectomy

van Limbergen et al Gastroenterology 2008

Assessment of IBD

• Confirm diagnosis with full work-up

• Evaluate extension

• Extra-intestinal signs or symptoms?

• Assess activity

• Check for immunization status

Evolution of Crohn’s Disease

J Cosnes et al. Gastroenterology, 2002

N=1448 N=1129

Crohn’s disease – Goals of treatment

• Mucosal healing

• Maintenance of remission

• Optimize growth

• Preserve quality of life

Children have a more active disease, require more immunossupression and have higher risk for the need of surgery

Crohn’s disease – Goals of treatment

• Mucosal healing

• Maintenance of remission

• Optimize growth

• Preserve quality of life

Children have a more active disease, require more immunossupression and have higher risk for the need of surgery

Need for pediatricians with

experience!

Induction of remission in CD

• Nutrition therapy is the first line treatment

• Exclusive enteral nutrition is the best option for luminal disease regardless of location

– Isolated oral or perianal disease my require alternative treatment

• Polymeric diet with whole protein is adequate

• EEN promotes mucosal healing

Enteral nutrition in Crohn’s disease

Dziechciarz P et al Alim Pharmcol Therap, 2007

How to give EEN

• No advantage of elemental over polymeric formulas

• Use oral if possible, or NG tube

• Use composition with 1-1.5kcal/kg

• Try to match individual preference of flavour

• Exclusive nutrition for 6-8 weeks, then taper over 2 weeks

• Water or gums allowed

• Need for motivation (doctor and patient)!

• Oral corticosteroids are a possible alternative

• Less expensive in the short term

• Side effects

• Prednisone – 1 mg/kg (max 40) once daily – 2-4 weeks with tapering of 8-12 weeks

• Budesonide less effective but possible option in mild luminal ileo-cecal/ascending colon disease (9-12 mg/d)

• Enemas may be used for distal disease

• Steroids must not be used for maintenance.

• Symptomatic relief but do not heal the mucosa

• Biologics (anti-TNFα monoclonal antibodies)

– Infliximab, Adalimumab

• In moderate to severe disease, refractory to immunomodulators

• Best option for perianal penetrating disease

– IFX 5 mg/kg at wk 1,2,6 then every 8 wk, iv

– ADA

• >40kg: 160 mg at wk 1, 80 mg at wk 2, then 40 mg every 2wk

• <40kg: 80 mg at wk 1, 40 mg at wk 2, then 20 mg every 2wk

• Biologics (anti-TNFα monoclonal antibodies)

– Infliximab, Adalimumab

• In moderate to severe disease, refractory to immunomodulators

• Best option for perianal penetrating disease

– IFX 5 mg/kg at wk 1,2,6 then every 8 wk, iv

– ADA

• >40kg: 160 mg at wk 1, 80 mg at wk 2, then 40 mg every 2wk

• <40kg: 80 mg at wk 1, 40 mg at wk 2, then 20 mg every 2wk

Important: Exclude TB carefully

before starting biologics.

Reactivation of infection may occur.

• There is no evidence of benefit for induction

• May be useful in some cases with very mild

disease

– 50 mg/kg/d

Maintenance treatment

• Thiopurines for maintenance of remission (steroid sparing)

• Thiopurine at diagnosis in children at risk for adverse outcomes (complications, disease severity and, extent and phenotype) – Azathioprine 2-3 mg/kg/d – 6-Mercaptopurine 1-1.5 mg/kg/d

• Methotrexate can be used as a primary maintenance therapy or as an alternative to thiopurines. – 15 mg/m2 (max 25mg) once a week, sc (oral?...) – Supplement with weekly folate (24-72h after MTX) – Contraindicated in pregnancy!

Use of thiupurines in Crohn’s disease

0 100 200 300 400 500 600

Days from start of remission

Controls

J Markowitz et al. Gastroenterology 2000

Maintenance treatment with thiopurines

• Check blood count regularly

• Stop if pancretitis occurs and do not re-start

• TPMT assay (activity/genetics)?

• Effect of treatment takes up to 3 months

– Not useful for induction of remission

• Sun protection !

Biologics for maintenance

• Scheduled maintenance should be continued after responding to induction with a biologic

• Patients with sustained remission should maintain scheduled anti-TNF therapy or switch to an immunomodulator if they were previously immunomodulator naive

• Combination with AZA may have higher risks for side effects

– Evaluate the risk benefit on an individual basis.

– If combination therapy is used for a first anti TNF, it should be for a limited time

• Monitor for infections!

S Kugathasan et al. Gastroenterology 2000

8 16 24 32 40 64

Weeks after IFX administration

CD <2y after dx (n=6) CD >2y after dx (n=8)

Inflammation is the main determinant of low bone mineral density in pediatric inflammatory bowel disease

M Paganelli et al Inflamm Bowel Dis 2007

Mod/Severe Mild Remission

Disease Activity (PCDA1)

Correlation between disease activity

and BMAD in patients with CD

p=0.03

Group A

Group B

Effect of infliximab on

bone mineral density

Inflammation and mineral density

A: IFX + B: IFX -

Onset Diagnosis Early disease Late disease

Modified from: B Pariente et al. Inflamm Bowel Dis 2011

Early intervention

Optimised treatment

Ongoing objective monitoring

Bowel damage and disability

Disease activity

Stenosis

Fistula/Abscess

Surgery

Siegel et al. Inflamm Bowel Dis, 2011

Internal penetrating disease

• Signs and symptoms – abdominal pain, fever, nausea and vomiting, diarrhea

and fistula

– Predominantly in the lower right quadrant

• Diagnosis – Blood counts and infection screen

– Imaging of the abdomen (US, CT and MR)

• Probable agents – Pseudomonas, Enterobacter, Klebsiella, E coli,

Enterococcus, Bacteroides, Peptostreptococcus

Treatment of internal penetrating disease

• Empiric antibiotics

– carbapenem (imipenem or meropenem), a b-lactam/b-lactamase-inhibitor combination (piperacillin-tazobactam or ticarcillin-clavulanate), or an advanced-generation cephalosporin (ceftazidime) with metronidazole

– Vancomycin should be used empirically if the patient has had recent cephalosporin exposure, a history of previous infection, or colonization with enterococcal organisms

• Drainage and culture of fluid

• Immunomodulators (long term)

• Biologics (after drainage)

• Surgery in refractory cases MD Pfefferkorn et al. JPGN, 2013

Classification of perianal fistulas

Perianal fistula evaluation and treatment

EF de Zoeten et al. JPGN 2013

Elective surgery in CD

• It is no longer a “last resource” solution

• Elective in limited segmental disease specially with growth failure.

Endoscopy in follow-up - CD

• Before starting biologics

– Look for TB and CMV in mucosa

• Objective:

– evaluate severity and exclude complications

– justify change of treatment

Guidelines for the management of IBD in UK. JPGN 2010 Guidelines for the management of inflammatory bowel disease in adults. Gut 2011 European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. JCC 2009

• 10 years after diagnosis or before transition to adult care

– involvment of 1 or more colonic segments

– Independentemently of disease activity

• objective:

– Screen for dysplasia

– Evaluate extension of the disease

NICE clinical guidelines, 2011

Endoscopy in follow-up - CD • After surgery:

– 1 year after ileal or ileocolonic ressection

– Even if asymptomatic

– Evaluation and classification according to Rutgeerts score (0-4)

– NOTE: check for simultaneous calprotectin (every 3 m afer surgery)

• objective: – Check for subclinical endoscopic relapse; indication for biologic if on

AZA, in score 3-4 (Rutgeerts)

– Reason for calprotectin: correlate with endoscopy and relaibility for monitoring

ECCO, 2010 P Rutgeerts et al. Inflamm Bowel Dis 2008 Rutgeerts et al. Gastrentrology 1990

• Patients on biologics: – After 5 years of treatment with clinical and biochemical remission

• objective: – Consider stoping biologics? – Individual basis consideration (avoid growth spur) – Evaluate mucosal healing

• Patients with growth failure on apparent remission • objective:

– Check disease activity and consider change of therapy

• Patients on apparent remission but with ongoing subjective complains • objective:

– Check disease activity and consider change of therapy

Induction of remission in UC

• Oral 5-ASA are recommended as first-line induction therapy for mild to moderately active pediatric

• Monotherapy with topical 5-ASA may be effective in selected children with mild to moderate proctitis (rare!)

• Combining oral 5-ASA with topical 5-ASA is more effective than oral alone

• Rectal 5-ASA is superior and should be preferred over rectal steroid therapy

Steroids to induce remission in UC

• Oral steroids are effective for inducing remission but not for maintaining remission

• Oral steroids are recommended in moderate disease or in those failing remission with optimal 5-ASA therapy

• Those with severe disease should be admitted for iv steroid therapy – Dose 1 mg/kg (max 40 mg) once daily

• Steroid dependency should not be tolerated

Maintenance of remission in UC

• Thiopurines are recommended for maintaining remission in frequently relapsing (2–3/year) or steroid-dependent disease

• Thiopurines are ineffective for induction of remission

• 5-ASA monotherapy in children responding to steroids

• Cyclosporine or tacrolimus started during an episode of acute severe colitis should be discontinued after 4 months, bridging to thiopurines

• Insufficient to recommend methotrexate in pediatric UC

Probiotics in UC?

• Probiotics may be considered in children with

mild UC intolerant to 5-ASA, or as an adjuvant

therapy in those with mild residual activity

despite standard therapy

Severe UC (PUCAI 65-80)

• Methylprednisolone iv – 1-1.5 mg/kg/d (max 60 mg) in 1-2 daily doses

– Fewer mineralocorticoid effect than hydrocortisone

• Antibiotics if suspected infection or toxic megacolon – Consider C diff especially if recent antibiotics taken

• Stop 5-ASA

• If severe pain investigate for perforation and toxic megacolon

Severe UC

• When discussing second-line therapy, surgery

must always be seriously considered

• In patients failing iv corticosteroids, calcineurin

inhibitors or infliximab is recommended

Efficacy of 2nd line treatment: meta-analysis of pediatric studies

Surgery in UC

• Elective colectomy may be indicated in children with active or steroid-dependent UC despite maximal treatment with 5-ASA, thiopurines, and anti-TNF therapy, or colonic dysplasia

• Restorative proctocolectomy (ileoanal pouch or ileal pouch-anal anastomosis), especially the J-pouch, is preferred over straight pull-through (ileoanal) or ileorectal anastomosis

• Laparoscopy can be used safely

Severe UC

• A child with PUCAI > 45 on day 3 should be prepared for second-line therapy

• PUCAI > 65 on day 5 should prompt initiation of second-line therapy

• Corticosteroids may be continued for additional 2–5 d in a child with a PUCAI of ≤ 60 and ≥ 35 points on day 5, before a decision on second-line therapy is made

• Those with PUCAI < 35 points on day 5 are unlikely to require second-line therapy

D Turner et al. ECCO-ESPGHAN consensus, AJG 2011

Initial diagnosis or flare Evaluate severity; Teach coping techniques

Induction of remission

Mild d (PUCAI 10-35)

5-ASA max dose Use enemas (may be enough in proctitis)

Response (7-14d)?

Add enemas and/or

probiotics

Disease controled

Prednisolone 1mg/kg 1x/d (max

40mg) + 5-ASA

Response 7-14d?

Reduce steroids in 10 weeks

Admit for iv steroids

Moderate d (PUCAI 40-60) Severe d (PUCAI 65-80)

Tacro or IFX?

D Turner et al ECCO-ESPGHAN consensus JPGN 2012

Maintenance of remission

5-ASA in all Probiotics?

Topical treatment in proctitis

If disease chronically active or recurrent (on 5-ASA), Thiopurines

If disease chronically active or recurrent (on thiopurines), IFX (or ADA)

If failure of biologics, without

alternative diagnosis, colectomy

Initial diagnosis or flare Evaluate severity; Teach coping techniques

Induction of remission

Mild d (PUCAI 10-35)

5-ASA max dose Use enemas (may be enough in

proctitis)

Response (7-14d)?

Add enemas and/or probiotics

Disease controled

Prednisolone 1mg/kg 1x/d (max

40mg) + 5-ASA

Response 7-14d?

Reduce steroids in 10 weeks

Admit for iv steroids

Moderate d (PUCAI 40-60) Severe d (PUCAI 65-80)

Tacro or IFX?

Endoscopy in follow-up - UC

• Before starting biologics

– Activity may prevent full colonoscopy (at least rectosigmoidoscopy)

– Check for CMV in mucosa

• Objective:

– Evaluate severity and exclude complications

– Justify change of treatment

ECCO, ESPGHAN, and the Pediatric IBD Porto Group, Am J Gastroenterol 2011 Guidelines for the management of inflammatory bowel disease in adults. Gut 2011 European evidence-based concensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. JCC 2009

Endoscopy in follow up - UC

• 8- 10 years after diagnosis or before transition to adult care – Left colitis and pancolitis (exclude proctitis) – Independentemently of disease activity – If associated Sclerosing cholangitis it must be done earlier

(1 year post diagnosis of PSC) – Multiple biopsies (and all suspitious lesions) – Chromo-endoscopy important

• objective:

– Screen for dysplasia – Evaluate extension of disease

ECCO. Gut 2011 NICE clinical guideline 118, 2011,(www.nice.org.uk/guidance/CG118)

Conclusions – treatment of IBD

• Induction and maintenance therapies differ

• Use treatment adjustments wisely

• Not yet evidence for “top-down” therapy in pediatric CD, but “quick step-up” reasonable

• Avoid steroids

• Monitor growth

• Consider measures against opportuistic infection

Conclusions – Follow up

• Inflammation markers

• Fecal calprotectin

• Endoscopic control when necessary

There is nothing permanent

except change!

Heraclitus

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